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Diagnosis & Clinical Characteristics

Patients with de novo missense mutations in SCN8A are generally found to have severe phenotypes characterized primarily by intractable early onset epilepsy with various neurodevelopmental manifestations. Because there are other causes of epilepsy with similar phenotypes, clinical findings alone cannot establish a firm diagnosis. It is necessary to perform sequence analysis to detect a heterozygous pathogenic mutation in the SCN8A gene. Identification of an SCN8A pathogenic variant may have important implications for medical management of the seizure disorder.

The diagnosis of SCN8A-related epilepsy is established in a proband with epileptic encephalopathy by identification of a de novo mutation in the gene SCN8A through molecular genetic testing. Among the first 100 patients (unpublished data) with epileptic encephalopathy and apparently de novo SCN8A mutations, all of the identified mutations are missense mutations with the exception of one splice-site mutation predicted to cause an in-frame deletion. Two cases were inherited from mosaic parents.

Molecular testing approaches can include use of:

A multi-gene epilepsy panel that includes SCN8A and other genes of interest (see Differential Diagnosis) is the most common method. Note: The genes included and sensitivity of multi-gene panels vary by laboratory and over time.

Whole exome sequencing. In contrast to sequencing tests that analyze one gene or small groups of related genes, whole exome sequencing simultaneously analyzes most of the exons or coding regions in the 22,000 genes of the human genome using next-generation sequencing techniques.

Clinical Characteristics

SCN8A-related epilepsy is an early-onset, intractable epilepsy characterized by multiple seizure types and developmental delay. De novo mutations in SCN8A have been reported in 50 individuals to date [SCN8A Reference]. The clinical suspicion of SCN8A related epilepsy is complicated by phenotypic overlap with other early onset epilepsy syndromes, and by the broad spectrum of severity. The most common clinical features are described below.

Seizures

Age of onset was reported for 48/50 patients and ranges from the first day of life to 22 months, with a median age of onset of 4 months (mean 4.7 months). The mothers of some patients notice unusual ‘‘drumming’’ in utero movements in the later stages of pregnancy [Singh et al 2015]. Initial seizure type varies at onset with most patients developing additional seizure types, including focal clonic seizures evolving to a bilateral convulsive seizure, afebrile tonic clonic seizures, tonic seizures, epileptic spasms, febrile seizures, and myoclonic seizures. Both convulsive and non-convulsive status epilepticus appear to be common [Larsen et al 2015]. Seizure frequencies range from hundreds per day to one per month or less.

Most patients have refractory seizures and require polytherapy. Early evidence suggests that sodium channel blockers are the best first line of attack in controlling seizures [Boerma et al 2015, Kong et al 2015b, Larsen et al 2015]; however, few patients are known to be controlled on a single medication.

EEG

While often normal, EEG at onset may show focal or multifocal epileptiform activity. Patients often develop an abnormal EEG showing moderate to severe background slowing and focal or multifocal sharp waves or spikes, most often in the temporal regions. Some patients show almost continuous delta slowing in the temporo-parietal-occipital regions, with superimposed beta frequencies and bilateral asynchronous spikes or sharp waves [Larsen et al 2015]

MRI

Most patients exhibit normal MRI brain scans at onset. Abnormal findings may include cerebral atrophy and hypoplasia of the corpus callosum. Some patients have been shown to develop cerebral or cerebellar atrophy in follow-up studies [Larsen et al 2015, Singh et al 2015].

Development

The developmental pattern varies from normal development prior to seizure onset with subsequent slowing or regression after seizure onset, to one of abnormal development from birth [Larsen et al 2015]. Many patients experience a drastic slowing or arrest in development after a known trigger (e.g., change in seizure type, vaccination) or for no apparent reason.

Approximately half of patients learn to sit and walk unassisted. Ataxia is common in these patients. The remaining patients are non-ambulatory. Patients can experience sudden loss of mobility.

Language is frequently affected. The majority of patients speak few words or none.

Intellectual Disability

Patients typically develop intellectual disability ranging from mild to severe, with about half of patients having severe intellectual disability. Autistic features are noted in some cases [Larsen et al 2015].

Movement Abnormalities

Variable types of movement disorders have been described in some patients, including hypotonia, dystonia, choreoathetosis, ataxia, spasticity, and increased startle.

Startle and Sleep Problems

Many children are hyper-alert as infants (i.e., more awake and aware of their surroundings than typical newborns) and are easily startled. Singh and colleagues [2015] reported one such case where the child was noted to have jittery movements shortly after birth, and a pathologically exaggerated startle response to tactile and acoustic stimuli, prompting a suspicion of hyperekplexia. The hyper-alert sleep appears to make it more difficult to settle into a deep, healthy sleep. These symptoms have been anecdotally reported in several other SCN8A cases.

Dravet syndrome is an infantile epileptic encephalopathy characterized by hemiclonic or generalized seizures that are often triggered by fever. More than 80% of patients with Dravet syndrome have de novo mutations in the related sodium channel gene SCN1A[Marini et al 2011] that result in loss of function due to protein truncation (60%) or missense mutations that inactivate the channel. The distinction between SCN1A and SCN8A mutations is important because sodium channel blockers should be avoided in Dravet syndrome, whereas they may be beneficial in SCN8A-related epilepsy (see Treatment of Manifestations).

Age of onset. The mean age of onset is similar but the range of 0 days to 22 months in SCN8A encephalopathy is broader than that seen in Dravet syndrome.

Febrile seizures. Susceptibility to seizures with fever is common in Dravet syndrome, but rare in SCN8A encephalopathy.

Infantile spasms. Many patients with SCN8A encephalopathy present with spasms, which are not a feature of Dravet syndrome.

Myoclonic seizures. Patients with SCN8A-related epilepsy rarely have myoclonic seizures, which are common in Dravet syndrome

Hypotonia and movement disorders are common in SCN8A patients, but are not typical of Dravet syndrome.

EEG findings. Generalized spike wave, a hallmark of Dravet syndrome after 1-2 years of age, is not typical in SCN8A encephalopathy.

Medications. Sodium channel blockers such as carbamazepine, oxcarbazepine, and phenytoin appear to be the most efficacious AED for SCN8A encephalopathy [Boerma et al 2015, Larsen et al 2015], while many Dravet syndrome patients do worse on sodium channel blockers.

Lennox-Gastaut syndrome (LGS)

LGS is an epileptic encephalopathy characterized by multiple, refractory seizure types, moderate to severe intellectual disability and slow spike and wave pattern on EEG. At least one patient with an initial diagnosis of LGS was found to have a de novo SCN8A mutation [Epi et al 2013].

Infantile spasms

Infantile spasms are a specific seizure type seen most commonly in West syndrome, a syndrome characterized by infantile spasms, the characteristic EEG pattern of hypsarrhythmia, and developmental delay. The etiology of infantile spasms is heterogeneous. There have been several genes identified in which mutations are associated with infantile spasms [Pavone et al 2014]. Several patients with de novo SCN8A mutations had infantile spasms as one of their seizure types.

Early infantile epileptic encephalopathy (EIEE 308350)

EIEE refers to a diverse group of disorders that are all characterized by refractory seizures and cognitive slowing or regression associated with ongoing epileptiform activity. There are 28 genes in which mutations are known to cause EIEE. The phenotypes of patients with EIEE due to mutations in different genes can overlap, making it difficult to determine the genetic etiology based on clinical presentation alone.